2001 Why the Lupus Immune System Reacts to Its Own DNA
Dr. Cohen’s research focused on understanding the behavior of important white blood cells known as scavenger cells. These cells act as the body’s ‘sanitation engineers,’ picking up worn out cells and disposing of them.
Dr. Cohen has discovered that a chemical normally found on the surface of the scavenger cells is important for enabling them to function properly. Without this chemical, animals develop a lupus-like disease.
“I am extremely grateful to the LRI for being brave enough to fund unusual work at an early stage of development. This initial funding was responsible for getting what is now a very large project off the ground.” – Dr. Cohen
His findings published in a 2002 issue of Journal of Experimental Medicine have had a significant impact on the field, with 60 citations to date. In the paper, Dr. Cohen reported that the clearance of apoptotic cells is delayed in c-mer deficient mice and that the mice develop a lupus-like autoimmunity.
“The mer work seems important in atherosclerosis research in general,” noted Dr. Cohen in 2010, “and has led to several groups from that area investigating this molecule.”
Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA. J Exp Med. 2002 Jul 1;196(1):135-40.
The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity. Behrens EM, Gadue P, Gong SY, Garrett S, Stein PL, Cohen PL. Eur J Immunol. 2003 Aug;33(8):2160-7.
Genetic models for the clearance of apoptotic cells. Cohen PL, Caricchio R. Rheum Dis Clin North Am. 2004 Aug;30(3):473-86, viii.
The Mer receptor tyrosine kinase is required for the loss of B cell tolerance in the chronic graft-versus-host disease model of systemic lupus erythematosus. Shao WH, Eisenberg RA, Cohen PL. J Immunol. 180(11):7728-35, 2008.
Defective Mer Receptor Tyrosine Kinase Signaling in Bone Marrow Cells Promotes Apoptotic Cell Accumulation and Accelerates Atherosclerosis. Ait-Oufella H, Pouresmail V, Simon T, Blanc-Brude O, Kinugawa K, Merval R, Offenstadt G, Lesèche G, Cohen PL, Tedgui A, Mallat Z. Arterioscler Thromb Vasc Biol. 2008 May 8. [Epub ahead of print]
The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. Shao WH, Zhen Y, Eisenberg RA, Cohen PL. Clin Immunol. 2009 Jul 23. [Epub ahead of print]
A Protective Role of Mer Receptor Tyrosine Kinase in Nephrotoxic Serum-induced Nephritis. Shao WH, Zhen Y, Rosenbaum J, Eisenberg RA, McGaha TL, Birkenbach M, and Cohen PL. Cinical Immunology, in press 2010
Dr. Cohen won funding from the U.S. Department of Veteran Affairs ($800,000) to examine the significance of these abnormalities in lupus. He also won an Alliance for Lupus Research award of $500,000 to test if human monoclonal antibodies to c-mer generated by phage display can be used to ameliorate the lupus effect seen in his (c-mer knockout) mouse model.
In 2009, human work related to the original project was funded as a part of the Philadelphia Autoimmunity Center of Excellence, based at Jefferson Medical College and at Temple University. Studies are ongoing to apply the basic mouse work to patients with lupus and other autoimmune disorders ($170,000 per year for 5 years).
Rev. July 2010